PROJECT SUMMARY The goal of this project is to understand the circuit mechanisms underlying neuronal sequence coordination across hippocampus and neocortex and their role in learning and memory. Cells that participated in a recent experience are reactivated in the form of ordered sequences that recapitulate behavior in a temporally compressed manner. These reactivations are coordinated by synchronous network events known as sharp-wave ripples (SWRs) that originate in the hippocampus and propagate to the neocortex. It has been proposed that SWRs and associated neuronal sequences mediate memory consolidation, planning and learning but a direct proof of these functions is still lacking. Additionally, several brain disorders characterized by learning and memory deficits have been related to disrupted SWRs. To guide behavior and decision making, the neocortex is believed to generalize across individual experiences encoded in the hippocampus to infer environmental regularities and rules. SWRs entrain neocortical activity, but how downstream cortical areas read out the hippocampal code transmitted during SWRs and use this information to guide goal-oriented behavior is unknown. I will perform silicon probe recordings and optogenetic manipulations in the hippocampus and its main cortical target regions of behaving rats and mice to test the functional role and circuit mechanisms of SWR sequences during the different phases of goal-oriented behavior. First, I will use a novel optogenetic approach for closed-loop manipulation of SWRs to directly test whether SWRs associated sequences support memory-guided behavior. My preliminary data supports the hypothesis that SWRs became longer with increased memory demands thus allowing extended replay events, and that those prolonged sequences are necessary and sufficient for memory-guided navigation and spatial learning. Second, I will examine the impact of SWRs on downstream cortical targets, in the context of goal-oriented spatial behavior. I will test if there is a specific functional topography of hippocampo-cortical interactions, with dorsal and ventral hippocampal SWRs propagating preferentially to retrosplenial and prefrontal cortices. I hypothesized that hippocampo ?cortical synchrony during SWRs will gradually increase with learning and that this process could lead to the generation of abstract representations, or schemas, in the cortex that will facilitate future decisions. Finally, I will test whether SWR-associated cortical sequences are locally generated or inherited from the hippocampus and how different classes of interneurons contribute to them. To achieve this, I will record and optogenetically manipulate different cell sub-types in transgenic mice. By using an innovative experimental approach, the proposed project will provide novel insights into the circuit mechanisms and behavioral role of neuronal sequences involved in learning and memory. This knowledge will also shed light into the mechanisms underlying memory deficits in neural disorders such as Alzheimer disease, schizophrenia and intellectual disability. It may also open new avenues for more targeted, closed-loop interventions in these disorders. The scientific skills developed during the training period of this project will be crucial for the accomplishment of the immediate scientific goals and become the pillars for the research I will develop in my future independent laboratory.